Resolution of Chronic Cough Following Treatment for Iron
Deficiency Anemia
A previously healthy 4-year-old female presented for a cough that
was not responsive to treatment of inhaled
corticosteroid (ICS). Pertinent history included meconium aspiration
with no respiratory support required and a course of confirmed
SARS-CoV-2 with fever and mild respiratory symptoms of a cough, that
resolved in 2-3 weeks. Child was seen in Allergy clinic 2 months before
first Pulmonary clinic appointment with a compliant of cough that
redeveloped. Cough was dry, associated with strenuous activity,
and noticeably present at night. She was started on albuterol 2
puffs every 4 hours, as needed.
At the one month follow up in Allergy clinic, cough remained present
with a mixed response to bronchodilator therapy. Given her history of
worsening cough at night and symptoms with activity, as well as a minor
family history of asthma, the patient was started on fluticasone 44 mcg,
2 puffs twice a day (BID). At that time, she was also referred
to pulmonary division for further workup and evaluation.
History obtained during pulmonary visit reaffirmed that obtained
from the patient’s previous allergy visits. In addition, there were no
reports of wheezing and whenever evaluated by a medical professional,
the child always sounded “clear.” Vitals were within normal limits
with a saturation of peripheral oxygen (SpO2) of 96%. A chest x-ray was
obtained showed nonspecific findings of reactive or viral airway disease
(Figure 1). Given that there was no improvement on the standard
dose ICS and the patient was too young to perform spirometry or fraction
exhaled nitric oxide (FENO) accurately, her therapy was
altered to combination ICS with long acting beta2-agonist (LABA).
Mometasone/formoterol 100/5 mcg 1 puff BID.
Four months later, there was almost complete resolution of nocturnal
cough and activity intolerance. However, she continued to have a
frequent dry cough during the daytime. As the patient was scheduled for
a direct laryngoscopy within the week of her pulmonary clinic visit, a
flexible bronchoscopy with bronchoalveolar lavage (BAL) was added
with blood work under sedation for a severe asthma workup, which
included a complete blood count (CBC) with differential and
immunoglobulin E (IgE).
Flexible bronchoscopy was unremarkable for visual findings other than
pale mucosa (Figure 1). Cultures showed no growth. Cytology showed a
neutrophil predominance of 50%, followed by macrophages at 33%, and
lymphocytes at 17%. Due to the fact lipid-laden macrophage index of 6
out of 200 and the absence of findings of cobblestone mucosa, aspiration
and reflux were unlikely to be attributing to her symptoms. Her blood
work resulted showing IgE of 66 [IU]/mL (Reference Range [RR]
0-75). The CBC was concerning for microcytic anemia with a hemoglobin
(Hgb) of 10.4 g/dL (RR 11.5-13.5 g/dL) and a hematocrit (Hct) of 32.6%
(RR 34.0-40.0%). The mean corpuscular volume (MCV) was low at 68.5 fL
(RR 75.0-87.0 fL) and she had a basophilia of 1.8% (RR 0.1-1.1%).
Ultimately, she was referred to hematology and was started on oral
ferrous sulfate at 3 mg/kg daily after finding her low ferritin of 4
ng/mL (RR 7-142 ng/mL). After 2 months of therapy, her symptoms of
cough completely resolved and family weaned her from the
ICS+LABA. Within 3 months after that, she had
normalized blood work. This included a Hgb 4.3 g/dL, Hct 43.8%, MCV
82.8 fL, and a ferritin of 52. She was then transitioned to a
multivitamin. At her follow up in pulmonary clinic two months after
discontinuing ICS+LABA, there were no respiratory complaints.
Cough is a common presenting symptom in
pediatrics[1]. This natural process that protects
the airways and occurs spontaneously or voluntarily. If lasting longer
than 4 weeks in the pediatric population, it is considered
chronic[2]. Common etiologies in children include:
asthma, protracted bronchitis, tracheomalacia, habit cough, and various
systemic disorders[2]. This case is unique due to
reported resolution of cough and ability to tolerate weaning off
of ICS+LABA following the identification and correction of iron
deficiency anemia (IDA).
Iron deficiency (ID) and IDA are very common diagnoses worldwide,
impacting 1-2 billion individuals a year. Occurring predominantly in
children, especially in low- to middle income
families[3]. Classically, ID is characterized with
fatigue, lethargy, difficulty concentrating, dizziness, tinnitus,
pallor, and headache[4]. While a cough hasn’t been
directly associated with ID, there is an association with nitric
oxide (NO) production[5], which is a modulator of
type 2 inflammation. It is increased in the exhaled breath of many
asthmatics with its concentrations widely recognized as a marker of
airway inflammation and measured via fractional concentration of exhaled
nitric oxide (FENO)[6,7]. Other than occurring in
patients with asthma, NO is known to be an important pathogenic effector
in pertussis and other respiratory tract diseases that are caused by
inflammation[8,9].
There are currently published reports of iron supplementation being
beneficial in the treatment of a cough associated with angiotensin
converting enzyme inhibitor (ACEI). This is due to decreased ACEI
induced generation of NO in bronchial epithelial cells. Iron has
the ability to inhibit the activity of NO synthase (NOS), the
heme-related enzyme involved in NO production[10].
Thus, suggesting that iron supplementation reduces the generation of NO
and may consequently abolish a dry cough[6].
Although other mechanisms by which ID may favor a lingering cough are
unknown, there have been findings of reduced epithelial airway thickness
in subjects with ID that suggests a cough could be favored by increased
mucosa permeability to irritative stimuli[10]. In
addition, plausible explanation includes ID acting to impair the defense
mechanisms of airway mucosa via physiologic changes[11]. It is known that ID weakens the defensive
response to injuries by impairing immune function, such as the
production of interleukin-2, a cytokine, which plays an important role
in maintaining the normal immune response[12].
In summary, while ID and IDA direct mechanisms for cough production are
unknown, there are known associations with physiologic changes in the
respiratory tract that may promote and extend the length of time for
a cough to persist. When the targeted therapy directly addressed to
the symptoms is not responding, there may be utility in the differential
assessment of standard blood work.
Swati Jayaram, MDa, Ethan Bassett,
MDc, Amanda Jacobson-Kelly, MDbd,
MScd, Rebecca Scherzer, MDbe, Eric
S. Mull, DOab
aDivision of Pulmonary Medicine;bDepartment of Pediatrics; cDivision
of Otolaryngology; dDivision of Hematology/Oncology;eDivision of Allergy and Immunology
Columbus, Ohio
Institution: Nationwide Children’s Hospital; Columbus, OH
Funding Source: None
Financial Disclosure: None
Conflicts of Interest: None
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